Single-cell transcriptomic analysis reveals cellular and molecular changes in EGFR-positive lung adenocarcinoma
Jian Chen1, Minghui Cai2, Lifei Meng1
1Department of Thoracic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China.
Background:
Lung adenocarcinoma (LUAD) frequently harbors activating mutations in the epidermal growth factor receptor (EGFR), making EGFR tyrosine kinase inhibitors (EGFR-TKIs) a critical component of targeted therapy. Although third-generation EGFR-TKIs, such as Furmonertinib, have improved outcomes for patients with EGFR-mutant LUAD, drug resistance and tumor adaptation remain major challenges. The cellular and molecular mechanisms underlying response and adaptation to Furmonertinib, particularly within the tumor microenvironment (TME), are not fully understood.
Methods:
We performed single-cell RNA sequencing on tumor and paired paracancerous tissues from EGFR-positive LUAD patients before and after Furmonertinib treatment, integrating both public and in-house datasets. We systematically analyzed changes in cellular composition, gene expression profiles, pathway enrichment, and ligand-receptor-mediated cell-cell communication.
Results:
Furmonertinib treatment led to a marked reduction in tumor cell proportion and profound remodeling of the TME. There was an increase in T cell infiltration, particularly CD4+ T cells, and a decrease in exhausted CD8+ T cells, indicating a shift toward a less immunosuppressive microenvironment. Cancer-associated fibroblasts and monocytes were also enriched post-treatment. Tumor cells exhibited increased EGFR expression, along with transcriptomic reprogramming characterized by upregulation of signaling, immune, and differentiation pathways, and downregulation of metabolic and protein synthesis genes. Cell-cell communication analysis revealed attenuation of immunosuppressive signaling (such as MIF axis) and enhancement of alternative ligand-receptor interactions, including LAMC1- and EGFR-related pathways.
Conclusions:
Our integrative single-cell analysis reveals that Furmonertinib therapy induces significant cellular and molecular changes in EGFR-positive LUAD, including TME remodeling, transcriptomic adaptation, and reprogramming of intercellular communication networks. These findings provide insight into the mechanisms of Furmonertinib response and resistance, and may inform strategies to optimize EGFR-TKI therapy.
Insights
Furmonertinib treatment reshapes the tumor microenvironment in EGFR-positive lung adenocarcinoma, altering immune cell populations and communication pathways. This adaptation offers insights into targeted therapy response and resistance mechanisms.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Lung adenocarcinoma (LUAD) often has EGFR mutations, making EGFR tyrosine kinase inhibitors (EGFR-TKIs) crucial.
- Third-generation EGFR-TKIs like Furmonertinib improve outcomes but face resistance.
- Mechanisms of Furmonertinib response and adaptation, especially in the tumor microenvironment (TME), require further study.
Purpose of the Study:
- To investigate the cellular and molecular changes in EGFR-positive LUAD after Furmonertinib treatment.
- To analyze the impact of Furmonertinib on the tumor microenvironment (TME) and intercellular communication.
- To elucidate mechanisms underlying response and resistance to Furmonertinib therapy.
Main Methods:
- Single-cell RNA sequencing of tumor and adjacent tissues from EGFR-positive LUAD patients before and after Furmonertinib treatment.
- Integration of public and in-house single-cell datasets.
- Systematic analysis of cellular composition, gene expression, pathway enrichment, and ligand-receptor interactions.
Main Results:
- Furmonertinib treatment reduced tumor cell proportion and remodeled the TME, increasing T cell infiltration and decreasing exhausted CD8+ T cells.
- Enrichment of cancer-associated fibroblasts and monocytes was observed post-treatment.
- Tumor cells showed increased EGFR expression and transcriptomic reprogramming, with altered signaling, immune, and differentiation pathways. Cell-cell communication shifted, attenuating immunosuppressive signaling and enhancing LAMC1- and EGFR-related pathways.
Conclusions:
- Furmonertinib therapy induces significant cellular and molecular changes in EGFR-positive LUAD, including TME remodeling and transcriptomic adaptation.
- Reprogramming of intercellular communication networks provides insight into Furmonertinib response and resistance.
- Findings may guide strategies for optimizing EGFR-TKI therapy in LUAD.
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